New Insights into Wnt–Lrp5/6–β-Catenin Signaling in Mechanotransduction

Mechanical loading is essential to maintain normal bone metabolism and the balance between bone formation and resorption. The cellular mechanisms that control mechanotransduction are not fully defined, but several key pathways have been identified. We discuss the roles of several components of the Wnt signaling cascade, namely Lrp5, Lrp6, and β-catenin in mechanical loading-induced bone formation. Lrp5 is an important Wnt co-receptor for regulating bone mass and mechanotransduction, and appears to function principally by augmenting bone formation. Lrp6 also regulates bone mass but its action might involve resorption as well as formation. The role of Lrp6 in mechanotransduction is unclear. Studies addressing the role of β-catenin in bone metabolism and mechanotransduction highlight the uncertainties in downstream modulators of Lrp5 and Lrp6. Taken together, these data indicate that mechanical loading might affect bone regulation triggering the canonical Wnt signaling (and perhaps other pathways) not only via Lrp5 but also via Lrp6. Further work is needed to clarify the role of the Wnt signaling pathway in Lrp5 and/or Lrp6-mediated mechanotransduction, which could eventually lead to powerful therapeutic agents that might mimic the anabolic effects of mechanical stimulation.